Use of 5-ht2 receptor antagonists for the treatment of sleep disorders

ABSTRACT

The invention relates to the use of 5-HT 2  receptor antagonists for the preparation of a medicament for extending both non-REM sleep an REM sleep.

The invention relates to the use of 5-HT₂ receptor antagonists for thepreparation of a medicament for extending both non-REM sleep and REMsleep.

Novel N-(indolecarbonyl)piperazine derivatives and processes for thepreparation thereof are disclosed in WO 01/07435. While being welltolerated, the substances exhibit, inter alia, actions on the centralnervous system and has valuable pharmacological properties. They havestrong affinity to 5-HT_(2A) receptors and have 5-HT_(2A)receptor-antagonistic properties.

WO 01/07435 furthermore discloses that the saidN-(indolecarbonyl)-piperazine derivatives are suitable both inveterinary and in human medicine for the treatment of functionaldisorders of the central nervous system and of inflammation. They can beused for the prophylaxis and the combating of the consequences ofcerebral infarction (apoplexia cerebri), such as strokes (here, forexample, trauma) and cerebral ischaemia, and for the treatment ofextrapyramidal-motor side effects of neuroleptics (for example dystonicsyndrome, of muscle stiffness induced by neuroleptics, tremor (includingsubstance-induced tremor forms) or extrapyramidal movement disorders),and of Parkinson's disease, including dopaminomimetic side effects ofconventional Parkinson's medicaments, for the acute and symptomatictherapy of Alzheimer's disease and for the treatment of amyotrophiclateral sclerosis. The substances are likewise suitable as therapeuticagents for the treatment of brain trauma (for example after headinjuries) or spinal cord trauma. However, they are particularly suitableas medicament active ingredient for anxiolytics, antidepressants,antipsychotics, neuroleptics, antihypertonics and/or for positivelyinfluencing obsessive-compulsive disorder (OCD), including anancasticspectrum disorders (obsessive-compulsive spectrum disorders, OCSD),anxiety states, panic attacks, psychoses, schizophrenia, anorexia,delusional obsessions, agoraphobia, migraine, sleep disorders, includingsleep apnoea, tardive dyskinesia, learning disorders, age-dependentmemory disorders, eating disorders, such as bulimia, drugs misuse(including disorders induced by substance abuse) and/or sexualdysfunctions.

They are furthermore suitable for the treatment of endocrinic diseases,such as hyperprolactinaemia, furthermore in vasospasms, hypertension,gastrointestinal diseases, cardiovascular diseases and extrapyramidalsymptoms, as described in WO 99/11641 on page 2, line 24-30. Inaddition, the N-(indolecarbonyl)piperazine derivatives are suitable forlowering the intraocular pressure and for the treatment of glaucoma.

Further uses of these N-(indolecarbonyl)piperazine derivatives aredescribed in WO 03/045392: thus, the substances are also suitable forthe treatment of obesity, sub-types of anxiety, sub-types ofschizophrenia and types of dementia of various origin and for thetherapy of aggression disorders, Parkinson's disease, attention deficitdisorders with hyperactivity and behavioural disorders. Finally, theycan be employed in supplementary treatment in low-dose neuroleptictreatment.

The present invention had the object of finding further valuablepharmaceutical uses for the above-mentioned N-(indolecarbonyl)piperazinederivatives.

Although the use of these compounds for the treatment of sleep disordersand sleep apnoea is disclosed in WO 01/07435; it has, however,surprisingly now been found that they have—in contrast to conventionalsleeping drugs—the pharmacologically important ability to extend bothcomponents of sleep, i.e. non-REM sleep (including slow-wave componentsthereof) and REM sleep.

Many people suffer from sleep disorders, which may on the one hand be asymptom of a disease, but on the other hand may also represent anindependent syndrome. Thirty per cent of adults suffer from sleepdisorders. Sleep disorders can manifest themselves in various ways:

Difficulties in falling asleep are characterised by the length of time aperson needs to fall asleep. If this time is more than thirty minutes,the expression difficulties in falling asleep can be used. The personconcerned then often lies awake for long periods, which in extreme casescan even last for hours.

If a patient suffers from premature awakening, the expressiondifficulties in staying asleep is used. However, this is only the caseif the awakening occurs within six hours three times a week. The sleepis then often described as superficial and non-refreshing.

The expression premature awakening is used if the person concernedfrequently wakes up much too early and then cannot fall asleep again.

The sleep of humans and many mammals, such as, for example, alsorodents, can be divided roughly into the two stages of REM (=rapid eyemovement) and non-REM, which occur alternately a number of times duringsleep. As the name suggests, the eyes move rapidly in the eye socketsunder the closed lids in the REM phase. This phase is the most intensivedreaming phase in humans. In non-REM sleep, a distinction is madebetween 4 stages, of which stages 3 and 4 are referred to as “slow-wavesleep”.

In order to achieve maximum refreshment during sleep, optimum sleeparchitecture is important, i.e. a balanced ratio between the two sleepphases. The total duration of sleep should be divided into theindividual sleep stages as follows: non-REM stage 1:  5% non-REM stage2: 50% non-REM stage 3 and 4: 20% REM: 25%

Whereas standard sleeping drugs merely extend the duration of non-REMsleep, with the duration of REM sleep remaining unchanged or even beingreduced, the compounds according to the invention also increase theduration of REM sleep, which results in improved sleep architecture. Bycontrast, products on the market—such as, for example, triazolam,zolpidem or zoplicon—even shorten REM sleep.

It has already been known for some time that non-REM sleep (inparticular the slow-wave components) in rats (Dugovic and Wauquier, Eur.J. Pharmacol. 137, 145-6, 1987) and also in humans (van Laar et al.,Psychopharmacology (Berlin). 154, 189-97, 2001) is extended by 5-HT₂receptor antagonists. However, it was unclear which receptor sub-type isresponsible for this effect. Initially, the 5-HT_(2C) receptor wasfavoured (Sharpley et al., Neuropharmacology 33, 467-71, 1994).

Later, WO 00/12090 disclosed a selective antagonist of the 5-HT_(2A)receptor,R-(+)-alpha-(2,3-dimethoxyphenyl)-1-(2-(4-fluorophenyl)ethyl)-4-piperidinemethanol,which is suitable, inter alia, for the treatment of sleep disorders,effecting, in particular, an extension of slow-wave phases 3 and 4 ofnon-REM sleep.

By contrast, it has been reported that although non-selective 5-HT_(2A)antagonists, such as nefazodone, extend REM sleep, the slow-wavecomponents of non-REM sleep remain unchanged (Sharpley and Cowen, Biol.Psychiatry 37, 85-98, 1995).

Although in thalidomide, which earlier used to be marketed under thename Contergan, a sleeping drug is known which likewise extends bothsleep phases, this substance is not, however, a 5-HT₂ receptorantagonist.

At the present point in time, no antagonist of the 5-HT₂ receptors isknown which is capable of extending both non-REM sleep and REM sleep.With the present invention, a novel active principle has thus been foundwhich opens up novel possibilities for extending sleep and thus novelforms of therapy of sleep disorders.

Use is preferably made here of the following compounds, which arecharacterised in greater detail in WO 01/07435—where appropriate in theform of one of the salts thereof:

(1H-indol-4-yl)-(4-phenethylpiperazin-1-yl)methanone,(1H-indol-4-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone,(1H-indol-4-yl)-[4-(2,5-dichlorothiophen-3-ylethyl)piperazin-1-yl]methanone,(3-formyl-1H-indol-5-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone,(1H-indol-6-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone,(1H-indol-6-yl)-[4-(thiophen-2-ylethyl)piperazin-1-yl]methanone,hydrochloride, F.(1H-indol-6-yl)-[4-(2,5-dichlorothiophen-3-ylethyl)piperazin-1-yl]-methanone,

(3-cyano-1H-indol-6-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone,(1H-indol-7-yl)-(4-phenethylpiperazin-1-yl)methanone,(1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone,(1H-indol-7-yl)-[4-(5-chlorothiophen-2-ylethyl)piperazin-1-yl]methanone,(3-formyl-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone,(3-cyano-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone,(2,3-dimethyl-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone,

(6,7,8,9-tetrahydro-5H-carbazol-3-yl)-(4-phenethylpiperazin-1-yl)methanone,

(3-formyl-1H-indol-6-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone,(1H-indol-6-yl)-[4-(5-chlorothiophen-2-ylethyl)piperazin-1-yl]methanone,(1H-indol-4-yl)-[4-(5-chlorothiophen-2-ylethyl)piperazin-1-yl]methanone,(3-cyano-1H-indol-5-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone,(3-cyano-1H-indol-7-yl)-[4-(naphth-2-ylethyl)piperazin-1-yl]methanone,(3-cyano-1H-indol-4-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone,(3-cyano-1H-indol-4-yl)-[4-(2-fluorophenethyl)piperazin-1-yl]methanone,(3-cyano-1H-indol-7-yl)-[4-(2-fluorophenethyl)piperazin-1-yl]methanone,(3-aminocarbonyl-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]-methanone,

(3-cyano-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone,(3-cyano-1H-indol-7-yl)-[4-(5-chlorothiophen-2-ylethyl)piperazin-1-yl]-methanone,(3-cyano-1H-indol-7-yl)-(4-phenethylpiperazin-1-yl)methanone,(3-cyano-1H-indol-7-yl)-[4-(2,4-difluorophenethyl)piperazin-1-yl]methanone.

For the purposes of the invention, particular preference is given to theuse of(3-cyano-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanoneand(3-aminocarbonyl-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]-methanone.

Very particular preference is given to(3-cyano-1H-indol-7-yl)-[4-(4-fluoro-phenethyl)piperazin-1-yl]methanone.

The present invention therefore relates to the use of 5-HT₂ receptorantagonists, in particular 5-HT_(2A) receptor antagonists, for thepreparation of a medicament for extending both non-REM sleep and REMsleep.

In this connection, it has been found that theN-(indolecarbonyl)piperazine derivatives according to the invention areparticularly suitable for the treatment of difficulties in fallingasleep and staying asleep and premature awakening in the morning.

The present invention therefore furthermore relates to the use of 5-HT₂receptor antagonists, in particular 5-HT_(2A) receptor antagonists, forthe preparation of a medicament for the treatment of difficulties infalling asleep and staying asleep and premature awakening in themorning.

The invention furthermore relates to the use of 5-HT₂ receptorantagonists for the preparation of a pharmaceutical preparationcomprising the active ingredient according to the invention andoptionally excipients and/or adjuvants and optionally further activeingredients.

The medicaments here can be converted into a suitable dosage formtogether with at least one solid, liquid and/or semi-liquid excipient oradjuvant and optionally in combination with one or more further activeingredient(s).

In the sleep therapy according to the invention, the 5-HT₂ receptorantagonists are generally administered analogously to knownpreparations, preferably in doses of between about 0.1 and 500 mg, inparticular between 5 and 300 mg, per dosage unit. The daily dose ispreferably between about 0.01 and 250 mg/kg, in particular between 0.02and 100 mg/kg, of body weight.

The 5-HT₂ receptor antagonists are preferably administered here in dosesof between about 1 and 500 mg, in particular between 5 and 100 mg, perdosage unit. The daily dose is preferably between about 0.02 and 10mg/kg of body weight. However, the specific dose for each particularpatient depends on a very wide variety of factors, for example on theefficacy of the specific compound employed, on the age, body weight,general state of health, sex, on the diet, on the time and method ofadministration, on the excretion rate, medicament combination andseverity of the particular disease to which the therapy applies. Oraladministration is preferred.

The 5-HT₂ receptor antagonists may also be employed together with otheractive ingredients, in particular other sleeping drugs, in the treatmentof the diseases mentioned.

The invention therefore also relates to the use of 5-HT₂ receptorantagonists in combination with one or more further sleeping drugs inthe sleep therapy described above.

Specific instructions for the synthesis of the 5-HTreceptor-antagonistic N-(indolecarbonyl)piperazine derivatives describedhere are given in WO 01/07435.

The pharmaceutical preparations according to the invention can beemployed as medicaments in human and veterinary medicine. Suitableexcipients are organic or inorganic substances which are suitable forenteral (for example oral), parenteral or topical administration and donot react with the novel compounds, for example water, vegetable oils,benzyl alcohols, polyethylene glycols, gelatine, carbohydrates, such aslactose or starch, magnesium stearate, talc, Vaseline. Suitable forenteral administration are, in particular, tablets, coated tablets,capsules, syrups, juices, drops or suppositories, suitable forparenteral administration are solutions, preferably oil-based or aqueoussolutions, furthermore suspensions, emulsions or implants, and suitablefor topical application are ointments, creams or powders. The novelcompounds may also be lyophilised and the resultant lyophilisates used,for example, for the preparation of injection preparations.

The preparations indicated may be sterilised and/or comprise adjuvants,such as lubricants, preservatives, stabilisers and/or wetting agents,emulsifiers, salts for modifying the osmotic pressure, buffersubstances, dyes, flavours and/or aroma substances. They can, ifdesired, also comprise one or more further active ingredients, forexample one or more vitamins.

The examples below relate to pharmaceutical preparations:

EXAMPLE A1 Injection Vials

A solution of 100 g of an active ingredient according to the inventionand 5 g of disodium hydrogenphosphate in 3 l of bidistilled water isadjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered,transferred into injection vials, lyophilised and sealed under sterileconditions. Each injection vial contains 5 mg of active ingredient.

EXAMPLE A2 Suppositories

A mixture of 20 g of an active ingredient according to the invention ismelted with 100 g of soya lecithin and 1400 g of cocoa butter, pouredinto moulds and allowed to cool. Each suppository contains 20 mg ofactive ingredient.

EXAMPLE A3 Solution

A solution is prepared from 1 g of an active ingredient according to theinvention, 9.38 g of NaH₂PO₄×2 H₂O, 28.48 g of NaH₂PO₄×12 H₂O and 0.1 gof benzalkonium chloride in 940 ml of bidistilled water. The pH isadjusted to 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE A4 Ointment

500 mg of an active ingredient according to the invention are mixed with99.5 g of Vaseline under aseptic conditions.

EXAMPLE A5 Tablets

A mixture of 1 kg of an active ingredient according to the invention, 4kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg ofmagnesium stearate is pressed to give tablets in a conventional mannerin such a way that each tablet contains 10 mg of active ingredient.

EXAMPLE A6 Coated Tablets

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE A7 Capsules

2 kg of an active ingredient according to the invention are introducedinto hard gelatine capsules in a conventional manner in such a way thateach capsule contains 20 mg of the active ingredient.

EXAMPLE A8 Ampoules

A solution of 1 kg of an active ingredient according to the invention in60 l of bidistilled water is transferred into ampoules, lyophilisedunder aseptic conditions and sealed under sterile conditions. Eachampoule contains 10 mg of active ingredient.

The action of the 5-HT₂ receptor-antagonisticN-(indolecarbonyl)piperazine derivatives according to the inventionmanifests itself as follows, as described using the example of(3-cyano-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone:

In experiments in which the brain waves of rats were recorded over 6hours during the dark phase, the inventors of the present patentapplication have found that(3-cyano-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1- yl]methanoneat a dose of 3 mg/kg per os causes a maximum increase in non-REM sleepof about 5 minutes per hour, whereas the average increase is about 4min/h.

The comparative substance triazolam, by contrast, extends non-REM sleepby 2 min/h at a dose of 0.1 mg/kg and by 6.5 min/h at a dose of 0.4mg/kg, which corresponds to the maximum effect in triazolam.

Under the same conditions, zolpidem extends non-REM sleep by 5 min/h at5 mg/kg and by 7 min/h at 10 mg/kg. Zoplicon (2.5-5 mg/kg) exhibits acomparable effect.

(3-Cyano-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanoneis thus comparable with the reference sleeping drugs in its ability toextend non-REM sleep.

However, there is an important difference between the compound accordingto the invention and the reference sleeping drugs with respect to theiraction on REM sleep. The standard sleeping drugs shorten this stage ofsleep: triazolam (0.1-1.6 mg/kg) by 0.3 to 2.1 min/h, zolpidem (5-10mg/kg) and zopiclon (2.5-5 mg/kg) by 0.3 to 1.6 min/h (the values relateto recording on rats for 6 hours during the dark phase). Thesedifferences emanate from a reduction in the duration of the individualREM phases (triazolam) or from a reduction in the number of these phases(zolpidem/zopiclon).(3-Cyano-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]-methanone,by contrast, extends REM sleep by an average of 0.8 min/h and with amaximum of 2 min/h. This results essentially from the increase in thenumber of REM episodes.

This property of(3-cyano-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanoneis thus unique and opens up novel possibilities for extending sleep, inparticular in the treatment of difficulties in falling asleep andstaying asleep and premature awakening in the morning.

The above-described efficacy of(3-cyano-1H-indol-7-yl)-[4-(4-fluorophen-ethyl)piperazin-1-yl]methanonein the treatment of the sleep disorders according to the invention canbe determined in vivo as follows.

EXAMPLE B Treatment of Rats with (3-cyano-1H-indol-7-yl)-[4-(4-fluoro-phenethyl)piperazin-1-yl]methanone, hydrochloride

In order to measure the brain waves, EEG electrodes are implanted intothe brain of anaesthetised rats. After a recovery time of 15 days, theseelectrodes are connected to an amplifier via a flexible cable, and thebrain waves of the non-anaesthetised animals are recorded over 12 hours.(3-Cyano-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanoneis dissolved in advance in a concentration of 0.1 ml/100 g of peanutoil. This solution (compound) or, for comparison, merely the solvent(vehicle) is administered orally to the test animals in a dose of 3mg/kg. From the filtered and amplified brain-wave signals, the sleepstages are evaluated via Fourier spectral analysis including certaincriteria. The REM and non-REM sleep stages can be identified withreference to the patterns. The experimental results are shown in Tables1 (effect of the substance) and 2 (significances of the measurementvalues). It becomes clear that(3-cyano-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanoneresults in a significant extension both of non-REM sleep and of REMsleep and that these extensions are significant. TABLE 1 Effect of(3-cyano-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl] methanoneon various sleep parameters of rats (average ± standard error). REMsleep NREM sleep Wakefulness Vehicle Compound Vehicle Compound VehicleCompound Total Time (min) 35.3 ± 2.2 45.3 ± 3.8 185.8 ± 7.9 232.8 ± 13.1497.6 ± 8.5  440.6 ± 15.1 Episode Duration 79.6 ± 3.6 93.1 ± 6.6 147.0 ±5.4 184.8 ± 9.5  457.2 ± 31.2 422.5 ± 29.3 (sec) REM Latency (min)  3.9± 0.1  5.2 ± 0.3 Inter-REM interval 29.6 ± 1.7 28.8 ± 3.0 (min)Total Time: Time over the measurement time period spent in therespective sleep stagesEpisode Duration: Mean duration of an episode of the respective sleepstageREM Latency: Period from the beginning of sleep to entry into the firstREM phaseInter-REM interval: Average time between the intervals in the REM stageCompound: Label for the animals which have received the test substance.Vehicle: Label for the animals which have only received the solvent.Wakefulness: State of being awake

This experiment is a crossover study. This means that one and the sameanimal receives either first solvent (vehicle) and then, after a waitingtime of one week, the test substance(3-cyano-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone(compound), or the administration is carried out in the reversesequence. TABLE 2 Significance of the values from Table 1. Precise pvalues from ANOVA for measurement value repetitions REM time 0.04 REMduration 0.1 (n.s.) NREM time 0.01 NREM duration 0.003 Wakefulness time0.005 Wakefulness duration 0.5 (n.s.) REM latency 0.0002 Inter-REMinterval 0.8 (n.s.)(n.s.) the respective measurement values from Table 1 are notsignificant

The measured values after vehicle or compound administration arecompared with one another using the statistical method of analysis ofvariance (ANOVA). The p value is a statistical measure of theprobability that a difference occurs by chance between the measurementvalues or is caused by the substance administration. According tointernational standards, a p value of below 0.05 is regarded as“significant”.

It is clear from FIG. 1 that in particular stages 3 and 4, which areregarded as slow-wave sleep, are extended in non-REM sleep. The curveshows the effect of(3-cyano-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanoneon the relative delta power in the rat EEG, expressed as the differencefrom the control level (dotted zero line), as a function of the time ofday. The term delta power or delta waves denotes the “slow” wavesrecorded in the EEG which are characteristic of slow-wave sleep stages.For each rat, the hour average after solvent (vehicle) treatment wasfirstly determined and subtracted from the value after substancetreatment. The relative delta power is significantly increased overall.

1. Use of 5-HT₂ receptor antagonists and physiologically acceptablesalts and solvates thereof for the preparation of a medicament forextending both non-REM sleep and REM sleep.
 2. Use according to claim 1,characterised in that the 5-HT₂ receptor antagonists are of the 5-HT2asub-type.
 3. Use of 5-HT2a receptor antagonists according to claim 2,selected from a group consisting of (a)(3-aminocarbonyl-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone,(b)(3-cyano-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanoneand physiologically acceptable salts and solvates thereof for thepreparation of a medicament for extending both non-REM sleep and REMsleep.
 4. Use of (3-cyano-1H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone and physiologically acceptablesalts and solvates thereof for the preparation of a medicament forextending both non-REM sleep and REM sleep.
 5. Use of 5-HT₂ receptorantagonists and physiologically acceptable salts and solvates thereofaccording to claim 1 for the preparation of a medicament for thetreatment of difficulties in falling asleep and staying asleep andpremature awakening in the morning.
 6. Use of 5-HT₂ receptor antagonistsand physiologically acceptable salts and solvates thereof according toclaim 1 in combination with one or more further sleeping drugs.